The overall objective of this investigation is to evaluate an approach to improve the tissue selectivity and hence the therapeutic index of fluorinated pyrimidines in treatment of solid tumors. Studies are proposed to establish the following factors which may determine the tissue selectivity of a 5-fluorouracil (FU) metabolic prodrug in an in vivo system: (1) To determine if the formation of 5-fluorodeoxyuridine monophosphate (FdUMP and 5-fluorouridine triphosphate (FUTP) from FU is rate-limited by the perfusion of the tissue. 2) To determine if the rate-limiting step of FdUMP and FUTP formation can be altered when an FU prodrug with a lower extraction ratio is used in place of FU. Three FU analogs, Beta-D-4'-hydroxy-ftorafur (OH-FT), 5'-deoxy-5-fluorouridine (dFUR), and ftorafur (FT) are included in the study. 3) To verify the pharmacokinetic model which allows a quantitative prediction of intracellular localization of FU generated from a metabolic prodrug in a tissue when the intrinsic clearance and the plasma, protein-binding of the prodrug are given. 4) To test if the antitumor activity and host tissue toxicity of FU can be altered by using its metabolic prodrugs such as OH-FT and dFUR which are targeted at preferential activation in the tumor cells. 5) To correlate the metabolism of FU, OH-FT, and dFUR in bone marrow, small intestine, and tumor cells with their pharmacokinetic parameters, and with their antitumor activity and host tissue toxicity. The intrinsic clearance of a drug in rat liver, small intestine, bone marrow and colon tumor will be established using in situ tissue perfusion technique and by the Vm/Km in in vitro metabolism studies. The intracellular FdUMP and FUTP pools will be determined using a newly established HPLC assay. The antitumor activity of FU, OH-FT, and dFUR in rat colon tumor will be measured by a decrease in tumor weight and/or an increase in average survival time. Their host tissue toxicity will be compared by their relative ability to inhibit the thymidylate synthetase. Results of these studies will hopefully provide a pharmacokinetic and pharmacological basis for design of future FU analogs with improved therapeutic index.